Cardiovascular disease is the leading cause of death and disability in older Americans. Results of studies in experimental animals have shown that with senescence there is a decline in myocardial fatty acid utilization (MFAU) and oxidation (MFAO) and a relative increase in glucose utilization (MGU). These metabolic changes are paralleled by a decline in mechanical function. During the current grant interval, we have confirmed these observations in humans. The goal of this renewal application is to identify potential mechanisms responsible for the age-related shift in myocardial substrate metabolism and relate them to changes in left ventricular (LV) function. The nitric oxide (NO) system and the peroxisome proliferator activated receptor alpha (PPAR alpha) are promising candidates that will be investigated. Our first hypothesis is that changes in substrate utilization in the aging heart are mediated, at least in part, by a decline NO production and that these changes are paralleled by a decline in LV function. We will prove or disprove this hypothesis by performing a series of fairly-complex experiments that utilize PET quantification of myocardial substrate metabolism and echocardiographic measurements of LV systolic anddiast01ic function under conditions designed to reduce NO production in younger subjects (using L-NMMA) and increase NO production in older subjects (using L-arginine). Our second hypothesis is that changes in myocardial substrate metabolism and LV function in the aging heart may be mediated, at least in part, via a decline in PPAR alpha-mediated responses. Thus, administration of a PPAR alpha agonist to older humans will result in an increase in MFAO and MFAU and a decline in MGU and that this metabolic shift will be paralleled by an improvement in LV function. Using the same imaging techniques we will measure myocardial substrate metabolism and function before and after the administration of the PPAR alpha partial agonist, gemfibrozil to healthy older subjects to prove or disprove this hypothesis. The results of these studies should further our understanding of the role of NO and PPAR alpha in modulating this age-dependent myocardial metabolic shift and its impact on LV function. As a result, potentially new targets could be identified for novel therapeutics designed to treat various cardiac disorders that increase with age and potentially slow the impact of aging on the human heart.